Synthesis of 11-cis-retinoids by hydrosilylation-protodesilylation of an 11,12-didehydro precursor: Easy access to 11- and 12-mono- and 11,12-dideuteroretinoids

Article abstract of DOI:10.1002/chem.201202260

An expeditious, highly efficient approach to 11-cis-retinoids was achieved by semihydrogenation of a readily available 11-yne precursor through a hydrosilylation-protodesilylation protocol. The complete chemo-, regio-, and syn-stereoselectivity of the method also allowed direct access to 11- and 12-monodeutero-, and 11,12-dideutero-11-cis-retinoids. The analogous trans series was not accessible by this route, and was synthesized by means of Hiyama coupling. Copyright

Full text of DOI:10.1002/chem.201202260

FULL PAPER
DOI: 10.1002/chem.201202260
Synthesis of 11-cis-Retinoids by Hydrosilylation–Protodesilylation of an
11,12-Didehydro Precursor: Easy Access to 11- and 12-Mono- and 11,12-
Dideuteroretinoids
Juliꢀn Bergueiro,[a] Javier Montenegro,[b] Carlos Saꢀ,[b] and Susana Lꢁpez*[a]
Abstract: An expeditious, highly efficient approach to 11-cis-retinoids was ach-
ieved by semihydrogenation of a readily available 11-yne precursor through a hy-
Keywords: cross-coupling · hydrosi-
drosilylation–protodesilylation protocol. The complete chemo-, regio-, and syn-
lylation · regioselectivity · retinoids ·
stereoselectivity of the method also allowed direct access to 11- and 12-monodeu-
semihydrogenation
tero-, and 11,12-dideutero-11-cis-retinoids. The analogous trans series was not ac-
cessible by this route, and was synthesized by means of Hiyama coupling.
Introduction
A retinoid is one of a group of natural or synthetic ana-
logues of trans-retinol (vitamin A, 1; Figure 1), many of
which have important biological activities of potential thera-
peutic value.[1] Vitamin A itself plays key roles during the
development of the embryo and in postnatal life.[2] Retinal-
dehydes act as the chromophores of photoreceptor proteins:
11-cis-retinal (2) binds to rhodopsin, the light-capturing
membrane protein involved in vision,[3] and trans-retinal (3)
is the chromophore of the light-harvesting device coupled to
the ion pumps of the Halobacteria.[4] Retinoic acid (4) and
9-cis-retinoic acid (5) are the natural ligands of the nuclear
receptor families RAR and RXR, which function as tran-
scription factors that influence cell proliferation and cell dif-
ferentiation processes.[5] Certain natural or synthetic reti-
noids have also found application in the treatment of der-
matological diseases and some types of cancer.[6]
Over the past few decades, a myriad of retinoid ana-
logues, including isotopomers, haloretinoids, hydro- and de-
hydroretinoids, demethylated and methyl-switched deriva-
tives, analogues with locked conformations and/or configura-
Figure 1. Representative natural retinoids.
tions, and arotinoids have been synthesized with the aim of
further understanding these complex biological processes.[7]
Among them, retinals enriched in 2H and 13C at specific
sites have allowed the use of noninvasive isotope-sensitive
techniques (e.g., resonance Raman, FTIR difference, or
solid-state magic-angle-spinning NMR spectroscopies) to
gather otherwise unobtainable information about structural
and functional details of visual pigments and their photo-
products. Moreover, since isotopic labeling does not change
steric and electronic properties, the chemical processes of
these proteins can be studied without perturbing their
native states at the atomic level.[8] For example, as part of a
comprehensive study that used retinals with deuterium in
the conjugated chain,[9] Mathies and Lugtenburg et al. em-
ployed [11-D]-, [12-D]-, and [11,12-D2]-retinals to carry out
a full vibrational analysis of the chromophore of rhodopsin
[a] J. Bergueiro, Prof. Dr. S. Lꢀpez
Departamento de Quꢁmica Orgꢂnica
Facultad de Quꢁmica
Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
Fax : (+34)981-591-014
E-mail: susana.lopez.estevez@usc.es
[b] Dr. J. Montenegro, Prof. Dr. C. Saꢂ
Centro Singular de Investigaciꢀn en Quꢁmica Biolꢀgica
y Materiales Moleculares (CIQUS)
Universidad de Santiago de Compostela (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202260.
À
and its first photoproduct bathorhodopsin around C11 C12.
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

The resonance Raman spectra revealed a relatively large
torsional distortion of the polyene chain of bathorhodopsin,
with a twisted 11-trans structure that is significantly pertur-
bed near C12 by an electrostatic interaction with an opsin
residue.[9c]
ing was necessary.[21] Similarly, anti-hydrosilylation, though
much less common, is selectively performed by several
ruthenium-based catalysts. Thus Trost et al.[22] has shown
that the cationic complex [Cp*RuACTHNUTRGNEUNG(MeCN)3]PF6 (Cp*=pen-
tamethylcyclopentadienyl) effects stereoselective trans addi-
tion of hydrosilanes to internal alkynes with complete regio-
selectivity for the product with silicon in the more sterically
demanding position (subsequent copper-mediated desilyla-
tion (CuI, TBAF, THF) cleanly affords the (E)-alkenes
under mild conditions); and Fꢅrstner et al.[23] have employed
this same catalyst for chemo- and stereoselective reduction
of cycloalkynes to (E)-cycloalkenes, although in this case
treatment in the dark with AgF in aqueous THF/MeOH was
required to avoid isomerization of the olefin during protode-
silylation. This method has also proven applicable to conju-
gated enyne substrates, with hydrosilylation occurring selec-
tively at the triple bond and leaving the preexisting olefin
intact,[24] although the reactivity of enynes is significantly
lower than that of ordinary alkynes and requires the reac-
tion to be conducted in neat silane by using a higher catalyst
loading.[25]
Prompted by the above examples, as part of our ongoing
research on the chemistry and biology of natural and syn-
thetic retinoids,[26] we decided to revisit the stereoselective
partial reduction of the 11-yne retinoid precursor 6 by inves-
tigating whether this handy hydrosilylation–protodesilyla-
tion strategy would allow us to obtain, at will, either 11-cis-
or all-trans-retinoids. This goal was ambitious, since none of
the substrates mentioned in the literature approach 6 in
complexity. If achieved, it would constitute the key step in
the simplest and most straightforward route to retinoids de-
scribed to date. It would also provide easy access to retinoid
derivatives with structural modifications in positions 11 and/
or 12, such as 11- and 12-mono- and 11,12-dideuterated cis-
and trans-retinals.
Although a number of efficient, stereocontrolled ap-
proaches to retinoids have already been reported,[7] with the
most recent ones based on metal-catalyzed cross-coupling
reactions,[10] the search for improved, polyvalent routes to
these unstable metabolites is still an exciting synthetic chal-
lenge that provides a test of emerging methodologies.
The semihydrogenation of a carbon–carbon triple bond is
a particularly valuable reaction in synthetic organic chemis-
try, and a variety of approaches have been developed that
perform this transformation stereoselectively. They include
heterogeneous and homogeneous catalytic hydrogenation as
well as noncatalytic methods: reduction by diimide or dis-
solving metals, hydroalumination, or the use of metal-hy-
dride/transition-metal halide combinations.[11] Classical hy-
drogenation with Lindlar catalyst is the easiest way to
obtain cis-alkenes,[12] whereas reduction with Li or Na in
liquid ammonia is the traditional method for the synthesis
of trans-alkenes.[13] However, most of these methods failed
to achieve reliable stereoselective partial reduction of 11,12-
didehydroretinol (6)[14] as an expeditious means of access to
11-cis- and all-trans-retinoids. Thus, although Oroshnik[15] re-
ported that catalytic semihydrogenation of 6 gave 11-cis-ret-
inol (1) in moderate yield, Negishi et al.[10a] subsequently
found that this reaction could not be performed with high
selectivity, and Nakanishi and co-workers[16a] reported that
the Lindlar catalyst gave variable results that depended on
the level of catalyst “poisoning”. Other systems such as
nickel boride bound to borohydride exchange resin and vari-
ous homogeneous catalytic systems have also failed to yield
the desired 11-cis-ene. The only successful method has hith-
erto been reaction of 6 with Cu/Ag-activated Zn dust in
methanol/water, although even this procedure fails to afford
total stereoselectivity (yield 85%, Z/E ratio 13:1 at
C11).[16,17]
The retrosynthetic analysis is shown in Scheme 1. Stereo-
divergent hydrosilylation of 11,12-didehydroretinol (6), by
using Rh or Pt catalysis for syn addition and Ru catalysis for
anti addition, would lead to the trisubstituted cis- and trans-
vinylsilanes 9 and 14 or their C12 regioisomers.[27] Subse-
quent fluoride-mediated protodesilylation, followed by oxi-
dation of the allylic alcohol, would provide the correspond-
ing cis- and trans-retinals. Use of deuterosilanes in the hy-
drosilylation step and/or deuterated water in the protodesi-
lylation step would afford analogues that would be isotopi-
cally labeled at positions 11, 12, or both.
Recently, an improved stereoselective partial reduction of
internal alkynes has been developed that makes use of hy-
drosilylation[18]–protodesilylation protocols by using a varie-
ty of transition-metal complexes. For syn-hydrosilylation,
platinum and rhodium catalysts are the most frequently em-
ployed. For example, Mori and co-workers[19] reported the
rhodium-catalyzed room-temperature hydrosilylation of in-
ternal alkynes with silane reagents that bear heteroatom
substituents (e.g., [{RhCl
(EtO)3SiH, THF); Nakao et al.[20] employed the homogene-
ous platinum catalyst ([Pt(dvds)(tBu3P)] (dvds=divinyltetra-
ACHTUNGERTN(NUNG cod)}2] (cod=cyclooctadiene),
Results and Discussion
N
ACHTUNGTRENNUNG
methyldisiloxane; Karstedtꢄs catalyst) to prepare trisubsti-
tuted (2-hydroxymethyl)phenylsilanes from symmetrical in-
ternal alkynes under very mild conditions (hexane, 08C);
and Alami used a heterogeneous Pt catalyst (PtO2) to syn-
thesize (Z)-stilbenes from diarylalkynes by means of a one-
pot cis-hydrosilylation–protodesilylation (n-tetrabutylammo-
nium fluoride (TBAF)) sequence, although in this case heat-
The common precursor 6 was synthesized in high yield by
Sonogashira cross-coupling ([PdCl2ACHTNUTRGNE(UNG PPh3)2], CuI, pyrroli-
dine, THF, 95%) of two readily available fragments:[26c] tri-
enyl iodide 7 and pentenynol 8. Some of the catalytic semi-
hydrogenation conditions mentioned above were then
screened, in most cases using two different silanes: triethoxy-
silane, which was envisaged as best suited for further elabo-
&
2
&
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 11-cis-Retinoids
FULL PAPER
Scheme 1. Retrosynthetic analysis.
ration of the product because of its reactivity;[22d] and ben-
zyldimethylsilane, which was expected to afford more stable
vinylsilanes. The results are summarized in Table 1.
with triethoxysilane was by contrast significantly less effi-
cient and gave 9a in only a moderate 62% yield. Notably, in
both cases the reaction not only generated just a single ster-
eoisomer, but also provided exquisite regioselectivity in
favor of the product with the silane on the less-hindered
carbon, C11.[28] This regiochemistry was deduced from the
splitting pattern of the olefinic proton resonances, two sin-
glets at d=6.00 and 6.28 ppm in 9b that corresponded to
H10 and H12, respectively. The 11-(E) configuration was un-
equivocally confirmed by NOE interaction be-
tween the H10 and Me13 signals.
For the syn addition, the soluble complex [Pt
ACHTUNGTRNE(NUNG dvds)-
ACHTUNGTRENNUNG(tBu3P)] was the first catalyst tried, by using conditions suc-
cessfully employed by our group in the hydrosilylation of
terminal enynes.[26e] Reaction of 6 with benzyldimethylsilane
in the presence of 0.5 mol% of the catalyst in THF at room
temperature gave 9b in an excellent 92% yield; reaction
The results obtained with rhodium catalysts
Table 1. Hydrosilylation of 11-yne retinoid 6.
were unexpected (Table 1). Reaction of 6 with the
neutral dimer [{RhClACTHNUTRGNE(UGN cod)}2] and triethoxysilane in
CH2Cl2 did not take place at all, despite this cata-
lyst having been strongly recommended for hydro-
silylation when heteroatom-containing silanes are
employed;[19] after 6 h at RT, only starting material
was recovered. Even more surprisingly, when this
and other neutral rhodium catalysts were used with
benzyldimethylsilane under the same experimental
conditions, chemoselectivity was reversed, the
major product being not the expected product 9b
but the O-silylated compound 11b, the result of
dehydrogenative coupling of the hydrosilane with
the alcohol.[29] Thus treatment of 6 with benzyldi-
methylsilane and [{RhClACHTUNGRTNEUNG(cod)}2] in CH2Cl2 led to a
41% yield of 9b and 11b in 30:70 ratio; and even
more remarkably, reaction with [{RhCp*Cl}2] af-
forded 11b as the only product in a practically
quantitative 98% yield (Table 1). This last result,
though not useful for our current goal, deserves
more thorough investigation because as far as we
know it is the first example of complete chemose-
lectivity for O-silylation versus C-silylation of an
alcohol that bears a triple bond. For instance, in
the synthesis of silyl ethers by Ru-catalyzed dehy-
drogenative coupling of hydrosilanes with alcohols,
alkynyl alcohols are hydrosilylated at the triple
bond faster than at the oxygen atom, and partial
hydrogenation was also observed in the case of ole-
finic alcohols.[30]
À
Entry
Catalyst
H Si
Reaction
Total yield [%]
(% ratio)[b]
product(s)[a]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
[Pt
[Pt
A
N
A
H
G
9a
9b
6
9b/11b
11b
9b
9a
9b/10b
9a
62
92
–
ACHTUNGTRENNUNG
E
H
N
R
HBnMe2Si
HBnMe2Si
HBnMe2Si
41 (30:70)
N
98
56
32
G
N
H
R
G
32 (90:10)
78
65 (40:60)
9
10
G
U
HACHTUNGTRENNUNG
R
E
HBnMe2Si
9b/10b
[a] Reactions were carried out with H Si (1.5 equiv) and catalyst (5ꢆ10À3 equiv) in
THF (Pt) or CH2Cl2 (Rh, Ru) for 6 h at RT. [b] Yields and ratios were calculated
from isolated products.
À
With 11-silyl-11-cis-retinoids 9 in hand, protode-
silylation was carried out by treatment with n-tet-
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

S. Lꢀpez et al.
dried TBAF+25% D2O[34] al-
lowed the deuterodesilylation
to run smoothly, in very good
yields and with quasi-complete
deuterium
incorporation
(Scheme 2).[35] As far as we
know, deuterosilylation reac-
tions with such high levels of
deuterium incorporation have
not hitherto been reported.[36]
Finally, oxidation of the al-
lylic alcohols (MnO2, Na2CO3,
CH2Cl2) afforded 11-cis-retinal
(2) and its 11-, 12-, and 11,12-
isotopomers in good yields
(Scheme 2).[37]
Next, trans-hydrosilylation
of the 11-yne retinoid 6 to the
11-silyl-11-trans-retinoids
14
(or their C12 regiosisomers)
was attempted under the Ru
Scheme 2. Synthesis of deuterated 11-cis-retinoids.
catalysis conditions described
by Trost and co-workers.[22]
rabutylammonium fluoride, which afforded 11-cis-retinol
(12) in 86% yield (Scheme 2). Although desilylation with
TBAF has been reported to require high temperatures[23] or
activation,[22] in our case the reaction ran fast and smoothly
under mild conditions (TBAF·3H2O, THF, 3 h, RT).
However, only 11-cis products that result from syn addition
to the triple bond were obtained (Table 1). Thus reaction
with triethoxysilane in CH2Cl2 in the presence of [Cp*Ru-
AHCTUNGRTEN(NGUN MeCN)3]PF6 afforded 9a as the only product, albeit in a
good 78% yield, and reaction with benzyldimethylsilane led
to a 40:60 mixture of 9b and regioisomer 10b, in which the
silicon is located on the more sterically hindered carbon
(65% combined yield). When other ruthenium complexes
were screened, including the sterically less demanding
We have also been able to carry out the hydrosilylation–
protodesilylation sequence in one pot (6, [PtACTHNUTRGENNUG(dvds)ACHTUNTGREN(NUNG tBu3P)],
HBnMe2Si, THF, then TBAF·3H2O) to obtain 12 in a re-
markable 81% yield (Scheme 2).[31]
Finally (as regards the syn-hydrosilylation), we used the
regioselectivity of this reaction to introduce hydrogen iso-
topes at positions 11 and/or 12. Reaction of 6 with benzyl-
deuterodimethylsilane (2HBnMe2Si)[32] and the platinum cat-
alyst in THF for 6 h at RT afforded the 12-deutero-11-silyl-
11-cis-retinol (12-D-9b) in excellent yield (95%), and subse-
quent protodesilylation under the aforementioned condi-
tions led to 12-deutero-11-cis-retinol (12-D-12), again in
good yield (83%; Scheme 2). 1H NMR spectroscopy con-
firmed the location of the isotope and established the extent
of deuteration as >95% in both cases, the H12 signal
having completely disappeared and the absence of H11,H12
coupling making the signal for H11 simpler (d=6.35 ppm, d,
J=12.1 Hz) than in undeuterated 12 (d=6.35 ppm, t, J=
11.8 Hz).
[CpRu
AHCTUNGTRENNUNG
ACHTUNGTRNE(NUNG MeCN)3]PF6 and Grubbꢄs carbene catalyst [Cl2-
discouraging: no trans-addition products were achieved,
only lower yields of 9a or 9b, or mixtures with higher 9b/
10b ratios (Table 1).[38]
Disappointed by this failure, we eventually prepared the
deuterated trans series by using our recently described poly-
valent approach to retinoids, which employs a Hiyama
cross-coupling reaction to construct the central single bond
of the polyene framework (Scheme 3).[26d,e] Thus hydro- or
deuterosilylation of enyne 8 and its isotopomer 5-D-8 under
the same reaction conditions as described above afforded
the 4- or 5-mono or 4,5-dideuterated (E,E)-5-silyl-pentadie-
nols 13 in very high yields and with complete incorporation
of deuterium. Hiyama coupling with trienyl iodide 7 ([Pd2-
Deuterodesilylation of 9b and 12-D-9b to obtain 11-deu-
tero-11-cis-retinol (11-D-12) and 11,12-dideutero-11-cis-reti-
nol (11,12-D2-12), respectively, proved much more laborious.
Several sets of conditions, including 1) treatment with com-
mercial TBAF·3H2O followed by workup with D2O, and
2) the use of alternative fluoride sources (AgF, CsF) in deu-
terated methanol,[23,33] led either to decomposition or poor
deuterium incorporation (60% according to integration of
the corresponding 1H NMR spectroscopic signals). After
considerable experimentation, we found that the use of
ACHTUGNTNERN(UNG dba)3]·CHCl3, TBAF·3H2O, THF; dba=dibenzylideneace-
tone) then gave trans-retinols 1, which were finally oxidized
to obtain the 11- or 12-mono or 11,12-dideuterated trans-ret-
inals 3.
Conclusion
We have developed an expeditious approach to 11-cis-reti-
noids on the basis of efficient, chemoselective net cis reduc-
&
4
&
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 11-cis-Retinoids
FULL PAPER
(1.5 mL) afforded 12-D-9b (96.1 mg,
95%, >95% 12-D as determined by
1H NMR spectroscopy).
General procedure for proto- or deu-
terodesilylation of retinols 9b and 12-
D-9b: TBAF·3H2O or TBAF+25%
D2O (2 equiv) was added dropwise
over
a solution of 9b or 12-D-9b
(1 equiv) in THF, and the mixture
was stirred for 3 h. Then H2O or D2O
was added, the reaction was diluted
with diethyl ether, then the organic
layer was washed with H2O and amo-
nium chloride, and dried with Na2SO4
(anhydrous). Solvents were removed
under vacuum and the crude was pu-
rified by column chromatography
(silica gel, 70:30 hexane/AcOEt) to
afford 11-cis-retinols (12, 12-D-12, 11-
D-12 or 11,12-D2-12, respectively) as
yellow oils.
Synthesis of 11-cis-retinol (12): Fol-
lowing the general procedure, reac-
tion of a solution of 9b (40 mg, 9.20ꢆ
10À2 mmol) in THF (2 mL) with
TBAF·3H2O (1.0m in THF, 184 mL,
Scheme 3. Synthesis of deuterated all-trans-retinoids.
0.184 mmol) afforded, after quench-
ing with H2O, 11-cis-retinol (12)
(22.7 mg, 86%). One-pot reaction: benzyldimethylsilane (42 mL,
0.264 mmol) was added dropwise to a solution of PtACTHNUGRTENUNG(dvds) (0.1m in xy-
tion of the readily available 11-yne precursor 6 by platinum-
catalyzed syn-hydrosilylation followed by fluoride-induced
protodesilylation. This sequence can be carried out in one
pot, and the complete regioselectivity of the hydrosilylation
allows selective introduction of deuterium at positions 11,
12, or both.
Application of this technique to the synthesis of other an-
alogues of biological interest (11- and 12-haloretinoids,[39]
11- and 12-alkylated retinoids,[40] and so on) is in progress
and will be reported in due course.
lenes, 17 mL, 1.76ꢆ10À3 mmol) and tBu3P (4 mL, 1.76ꢆ10À3 mmol) in THF
(2 mL) and the mixture was stirred for 30 min. A solution of 6 (50.0 mg,
0.176 mmol) in THF (2 mL) was then added over 5 min and the reaction
mixture was stirred for 30 min. TBAF·3H2O (1.0m in THF, 704 mL,
0.704 mmol) was added and reaction mixture was stirred for 1 h and
quenched with H2O. The organic layer was diluted with ether, washed
with H2O and ammonium chloride, and dried with Na2SO4 (anhydrous).
Solvents were removed under vacuum and the crude was purified to
afford 12 (40.8 mg, 81%).
Synthesis of 11-cis-11-deuteroretinol (11-D-12): Following the general
procedure, reaction of a solution of 9b (20.0 mg, 4.60ꢆ10À2 mmol) in
THF (1 mL) with TBAF+25% D2O (1.0m in THF, 46 mL, 4.60ꢆ
10À2 mmol) afforded, after quenching with D2O (5 mL), 11-cis-11-deuter-
oretinol (11-D-12) (11.1 mg, 84%, >95% 11-D as determined by
1H NMR spectroscopy).
Experimental Section
All the solutions employed were degassed by bubbling argon for 15 min.
Reactions and purification of retinoids were carried out in the absence of
light.
Synthesis of 11-cis-12-deuteroretinol (12-D-12): Following the general
procedure, reaction of a solution of 12-D-9b (40.0 mg, 9.18ꢆ10À2 mmol)
in THF (2 mL) with TBAF·H2O (1.0m in THF, 185 mL, 0.185 mmol) af-
forded, after quenching with H2O (10 mL), 12-D-12 (21.8 mg, 83%,
General procedure for hydro- and deuterosilylation of 11,12-dehydroreti-
nol (6): A solution of 11,12-didehydroretinol (6) (1 equiv) in THF was
1
>95% 12-D as determined by H NMR spectroscopy).
added over a solution of catalyst {[Pt
[{RhCp*Cl2}2], Grubbs first-generation catalyst or [RuCp*AHCTUNGTRENNUNG
(dvds)
R
(cod)}2],
Synthesis of 11-cis-11,12-dideuteroretinol (11,12-D2-12): Following the
general procedure, reaction of a solution of 12-D-9 (50.0 mg, 0.115 mmol)
in THF (2 mL) with TBAF+25% D2O (1.0m in THF, 115 mL,
0.115 mmol) afforded, after quenching with D2O (5 mL), 11-cis-11,12-di-
deuteroretinol (11,12-D2-12) (26.6 mg, 84%, >95% 11,12-D2 as deter-
(5ꢆ10À3 equiv), and hydro- or deuterosilane (1.5 equiv) in THF or
CH2Cl2, and the resulting mixture was stirred for 6 h. Solvents were re-
moved under vacuum, and the crude was purified by column chromatog-
raphy (silica gel, 70:30 hexane/AcOEt) to afford silylretinoids 9, or 10,
and/or 11,12-dehydroretinyl benzyldimethylsilyl ether (11) as light yellow
oils.
1
mined by H NMR spectroscopy).
General procedure for the synthesis of (2E,4E)-dienylsilanes 13, 5-D-13,
4-D-13, and 4,5-D2-13: Benzyldimethylsilane or benzyldeuterodimethylsi-
Synthesis of (11E)-11-benzyldimethylsilylretinol (9b), Pt catalyzed: Fol-
lane (1.0–1.5 equiv) was added dropwise to a solution of PtACTHNGUETRNNU(G dvds) (0.1m
lowing the general procedure, treatment of a solution of Pt
N
in xylenes, 5ꢆ10À3 equiv) and tBu3P (5ꢆ10À3 equiv) in THF
(3 mLmmolÀ1), and the mixture was stirred for 30 min. A solution of
enynol 8 or 5-D-8 (1 equiv) in THF was then added over 10 min and the
reaction mixture was stirred for 1–2 h. The solvent was removed under
vacuum and the crude was purified by column chromatography (silica
gel, 70:30 hexane/AcOEt) to afford (2E,4E)-dienysilanes 13 as yellow
oils.
Synthesis of (11E)-11-benzyldimethylsilyl-12-deuteroretinol (12-D-9b),
Pt catalyzed: Following the general procedure, treatment of a solution of
Pt
10À3 mmol), and benzyldeuterodimethylsilane (56 mL, 0.348 mmol) in
THF (1.5 mL) with solution of (66.1 mg, 0.232 mmol) in THF
ACHTUNGTRENNUNG
(dvds) (0.1m in xylenes, 20 mL, 2.32ꢆ10À3 mmol), tBu3P (5 mL, 2.32ꢆ
Synthesis of (2E,4E)-5-(benzyldimethylsilyl)-3-methylpenta-2,4-dien-1-ol
(13): Following the general procedure, reaction of PtACTHNGUTERN(UNG dvds) (0.1m in xy-
a
6
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

S. Lꢀpez et al.
lenes, 50 mL, 5ꢆ10À3 mmol), tBu3P (1 mL, 4ꢆ10À3 mmol), benzyldimethyl-
silane (229 mL, 1.45 mmol), and 8 (107 mg, 1.11 mmol) in THF (2 mL) af-
forded compound 13 (284 mg, 97%).
Acknowledgements
We thank the MICINN (projects CTQ2011-28258 and Consolider Ingenio
2010 (CSD2007-00006)) for financial support. J.B. thanks the Xunta de
Galicia and MICINN for predoctoral grants.
Synthesis of (2E,4E)-5-(benzyldimethylsilyl)-5-deutero-3-methylpenta-
2,4-dien-1-ol (5-D-13): Following the general procedure, reaction of Pt-
ACHTUNGTRENNUNG
(dvds) (0.1m in xylenes, 313 mL, 3.13ꢆ10À2 mmol), tBu3P (8 mL, 3.13ꢆ
10À2 mmol), benzyldimethylsilane (744 mL, 4.70 mmol), and 5-D-8
(300 mg, 3.13 mmol) in THF (6 mL) afforded compound 5-D-13 (527 mg,
[1] a) The Retinoids: Biology, Chemistry and Medicine (Eds.: M. B.
Sporn, A. B. Roberts, D. S. Goodman), Raven, New York, 1994;
b) R. Blomhoff, H. K. Blomhoff, J. Neurobiol. 2006, 66, 606–630.
[2] a) R. Blomhoff, M. H. Green, T. Berg, K. R. Norum, Science 1990,
250, 399–404; b) J. L. Napoli in Encyclopedia of Biological Chemis-
try, Vol. 4 (Eds.: W. J. Lennarz, D. M. Lane), Elsevier, Oxford, 2004,
pp. 354–359.
[3] a) K. Palczewski, Ann. Rev. Biochem. 2006, 75, 743–767; b) K. P.
Hofmann, P. Scheeerer, P. W. Hildebrand, H. Choe, J. H. Park, M.
Heck, O. P. Ernst, Trends Biochem. Sci. 2009, 34, 540–552; c) S. O.
Smith, Ann. Rev. Biophys. 2010, 39, 309–328; d) J. von Lintig, P. D.
Kiser, M. Golczak, K. Palczewski, Trends Biochem. Sci. 2010, 35,
400–410; e) S. Sekharan, K. Morokuma, J. Am. Chem. Soc. 2011,
133, 19052–19055.
1
96%, >95% 5-D as determined by H NMR spectroscopy).
Synthesis of (2E,4E)-5-(benzyldimethylsilyl)-4-deutero-3-methylpenta-
2,4-dien-1-ol (4-D-13): Following the general procedure, reaction of Pt-
ACHTUNGTRENNUNG
(dvds) (0.1m in xylenes, 208 mL, 2.08ꢆ10À2 mmol), tBu3P (5 mL, 2.08ꢆ
10À2 mmol), benzyldeuterodimethylsilane (494 mL, 3.12 mmol), and
8
(200 mg, 2.08 mmol) in THF (4 mL) afforded compound 4-D-13 (479 mg,
1
93%, >95% 4-D as determined by H NMR spectroscopy).
Synthesis of (2E,4E)-5-(benzyldimethylsilyl)-4,5-dideutero-3-methylpen-
ta-2,4-dien-1-ol (4,5-D2-13): Following the general procedure, reaction of
PtACHTUNGTRENNUNG
(dvds) (0.1m in xylenes, 313 mL, 3.13ꢆ10À2 mmol), tBu3P (8 mL, 3.13ꢆ
10À2 mmol), benzyldeuterodimethylsilane (744 mL, 4.70 mmol), and 5-D-8
(300 mg, 3.13 mmol) in THF (6 mL) afforded compound 4,5-D2-13
(501 mg, 91%, >95% 4,5-D2 as determined by 1H NMR spectroscopy).
[4] a) J. K. Lanyi, H. Luecke, Curr. Biol. Curr. Op. Struct. Biol. 2001, 11,
415–419; b) J. K. Lanyi, Ann. Rev. Physiol. 2004, 66, 665–688;
c) J. K. Lanyi, Biochim. Biophys. Acta Bioenerg. 2006, 1757, 1012–
1018.
[5] a) D. J. Mangelsdorf, C. Thummel, M. Beato, P. Herrlich, G. Schꢅtz,
K. Umesono, B. Blumberg, P. Kastner, M. Mark, P. Chambon, R. M.
Evans, Cell 1995, 83, 835–839; b) L. Altucci, M. D. Leibowitz, K. M.
Ogilvie, A. R. de Lera, H. Gronemeyer, Nat. Rev. Drug Discovery
2007, 6, 793–810; c) V. Duong, C. Rochette-Egly, Biochim. Biophys.
Acta Mol. Basis Dis. 2011, 1812, 1023–1031; d) S. ꢇlvarez, W. Bour-
guet, H. Gronemeyer, ꢇ. R. de Lera, Expert Opin. Ther. Pat. 2011,
21, 55–63.
General procedure for the Hiyama cross-coupling of organosilicon com-
pounds 13, 5-D-13, 4-D-13, and 4,5-D2-13 with trienyl iodide 7:
TBAF·3H2O (1.0m in THF, 2 equiv) was added dropwise to a solution of
dienyl silanes 13, 5-D-13, 4-D-13, or 4,5-D2-13 (1.5 equiv) in THF
(20 mLmmolÀ1) and the reaction was stirred for 30 min. A solution of tri-
enyl iodide 7 (1 equiv) in THF and [Pd2ACTHNUTRGNEUNG
(dba)3]·CHCl3 (5ꢆ10À2 equiv)
were sequentially added, and the reaction was stirred for 1 h. The mix-
ture was diluted with diethyl ether and filtered through a short pad of
silica gel. The solvent was removed under vacuum and the crude was pu-
rified by column chromatography (SiO2, 70:30 hexane/AcOEt) to afford
the corresponding all-trans-retinols (1, 11-D-1, 12-D-1, 11,12-D2-1) as
yellow oils.
[6] a) L. W. Spruce, J. B. Gale, K. D. Berlin, A. K. Verma, T. R. Breit-
man, X. Ji, D. van der Helm, J. Med. Chem. 1991, 34, 430–439;
b) W. Bollag, E. E. Holdener, Ann. Oncol. 1992, 3, 513–526;
c) D. M. Benbrook, M. M. Madler, L. W. Spruce, P. J. Brickbichler,
E. C. Nelson, S. Subramanian, G. M. Weerasekare, J. B. Gale, M. K.
Patterson, Jr., B. Wang, W. Wang, S. Lu, T. C. Rowland, P. DiSives-
tro, C. Lindamood III, D. L. Hill, K. D. Berlin, J. Med. Chem. 1997,
40, 3567–3583; d) K. H. Dragnev, J. R. Rigas, E. Dmitrovsky, Oncol-
ogist 2000, 5, 361–368; e) S. J. Freemantle, K. H. Dragnev, E. Dmi-
trovsky, J. Natl. Canc. Inst. 2006, 98, 426–427.
[7] For significant reviews on the synthesis of retinoids, see: a) R. S. H.
Liu, A. E. Asato, Tetrahedron 1984, 40, 1931–1969; b) “The Synthet-
ic Chemisry of Retinoids”: M. I. Dawson, P. D. Hobbs, The Reti-
noids: Biology, Chemistry and Medicine (Eds.: M. B. Sporn, A. B.
Roberts, D. S. Goodman), Raven, New York, 1994; c) B. Domꢁ-
nguez, R. Alvarez, A. R. de Lera, Org. Prep. Proced. Int. 2003, 35,
239–306; d) J. H. Barnard, J. C. Collings, A. Whiting, S. A. Prybor-
ski, T. B. Marder, Chem. Eur. J. 2009, 15, 11430–11442; e) R. S. H.
Liu, J. Liu, J. Nat. Prod. 2011, 74, 512–517.
[8] a) M. Groesbeek, J. Lugtenburg, Photochem. Photobiol. 1992, 56,
903–908; b) J. Lugtenburg, Eur. J. Clin. Nutr. 1996, 50, S17–S20;
c) J. Lugtenburg, A. F. L. Creemers, M. A. Verhoeven, A. A. C. van
Wijk, P. J. E. Verdegem, M. C. F. Monnee, F. J. H. M. Jansen, Pure
Appl. Chem. 1999, 71, 2245–2251; d) A. V. Struts, G. F. J. Salgado,
K. Tanaka, S. Krane, K. Nakanishi, M. Brown, J. Mol. Biol. 2007,
372, 50–66; e) P. B. S. Dawadi, J. Lugtenburg, Molecules 2010, 15,
1825–1872.
[9] a) G. Eyring, B. Curry, R. Mathies, A. Broek, J. Lugtenburg, J. Am.
Chem. Soc. 1980, 102, 5390–5392; b) A. D. Broek, J. Lugtenburg,
Recl. Trav. Chim Pays-Bas 1980, 99, 363–366; c) A. D. Broek, J.
Lugtenburg, Recl. Trav. Chim Pays-Bas 1982, 101, 102–105; d) G.
Eyring, B. Curry, A. Broek, J. Lugtenburg, R. Mathies, Biochemistry
1982, 21, 384–393; e) J. A. Pardoen, E. M. M. van den Berg, C.
Winkel, J. Lugtenburg, Recl. Trav. Chim Pays-Bas 1986, 105, 92–98;
f) I. Palings, J. A. Pardoen, E. van den Berg, C. Winkel, J. Lugten-
burg, R. A. Mathies, Biochemistry 1987, 26, 2544–2556; g) I. Palings,
Synthesis of trans-retinol (1): Following the general procedure, treatment
of a solution of dienylsilane 13 (31.6 mg, 9.61ꢆ10À2 mmol) in THF
(1 mL) with TBAF·3H2O (1.0m in THF, 128 mL, 0.128 mmol) for 30 min,
followed by addition of a solution of iodide 7 (20 mg, 6.43ꢆ10À2 mmol)
in THF (1 mL) and [Pd2ACHTUNGTRENNUNG
(dba)3]·CHCl3 (2 mg, 2.12ꢆ10À3 mmol), afforded
compound 1 (18 mg, 77%).
Synthesis of trans-11-deuteroretinol (11-D-1): Following the general pro-
cedure, treatment of
a solution of dienylsilane 5-D-13 (117 mg,
0.474 mmol) in THF (1 mL) with TBAF·3H2O (1.0m in THF, 632 mL,
0.633 mmol) for 30 min, followed by addition of a solution of iodide 7
(100 mg, 0.317 mmol) in THF (1 mL) and [Pd2ACHTNUTRGNE(UGN dba)3]·CHCl3 (7.2 mg,
7.91ꢆ10À3 mmol), afforded compound 11-D-1 (72.7 mg, 80%, >95% 11-
1
D as determined by H NMR spectroscopy).
Synthesis of trans-12-deuteroretinol (12-D-1): Following the general pro-
cedure, treatment of
a solution of dienylsilane 4-D-13 (117 mg,
0.474 mmol) in THF (1 mL) with TBAF·3H2O (1.0m in THF, 632 mL,
0.633 mmol) for 30 min, followed by addition of a solution of iodide 7
(100 mg, 0.317 mmol) in THF (1 mL) and [Pd2ACHTNUTRGNE(UGN dba)3]·CHCl3 (7.2 mg,
7.91ꢆ10À3 mmol), afforded compound 12-D-1 (74.5 mg, 82%, >95% 12-
1
D as determined by H NMR spectroscopy).
Synthesis of trans-11,12-dideuteroretinol (11,12-D2-1): Following the gen-
eral procedure, treatment of a solution of dienylsilane 4,5-D2-13 (170 mg,
0.683 mmol) in THF (1 mL) with TBAF·3H2O (1.0m in THF, 911 mL,
0.911 mmol) for 30 min, followed by addition of a solution of iodine 7
(144 mg, 0.455 mmol) in THF (1 mL) and [Pd2ACHTNUTRGNE(UNG dba)3]·CHCl3 (10.4 mg,
1.14ꢆ10À2 mmol), afforded compound 11,12-D2-1 (103 mg, 78%,>95%
1
11,12-D2 as determined by H NMR spectroscopy).
&
6
&
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 11-cis-Retinoids
FULL PAPER
E. M. M. van den Berg, J. Lugtenburg, R. A. Mathies, Biochemistry
1989, 28, 1498–1507; h) H. Deng, D. Manor, G. Weng, P. Rath, Y.
Koutalos, T. Ebrey, R. Gebhard, J. Lugtenburg, M. Tsuda, R. H.
Callender, Biochemistry 1991, 30, 4495–4502; i) L. Huang, H. Deng,
Y. Koutalos, T. Ebrey, M. Groesbeek, J. Lugtenburg, M. Tsuda,
R. H. Callender, Photochem. Photobiol. 1997, 66, 747–754.
[20] Y. Nakao, H. Imanaka, J. Chen, A. Yada, T. Hiyama, J. Organomet.
Chem. 2007, 692, 585–603.
[21] A. Giraud, O. Provot, A. Hamzꢈ, J.-D. Brion, M. Alami, Tetrahe-
dron Lett. 2008, 49, 1107–1110.
[22] a) B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2001, 123, 12726–
12727; b) B. M. Trost, Z. T. Ball, T. Jçge, J. Am. Chem. Soc. 2002,
124, 7922–7923; c) B. M. Yrost, Z. T. Ball, T. Jçge, Angew. Chem.
2003, 115, 3537–3540; Angew. Chem. Int. Ed. 2003, 42, 3415–3418;
d) B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2005, 127, 17644–
17655.
[23] a) A. Fꢅrstner, K. Radkowski, Chem. Commun. 2002, 2182–2183;
b) F. Lacombe, K. Radkowski, G. Seidel, A. Fꢅrstner, Tetrahedron
2004, 60, 7315–7324.
[10] For pioneering work on the synthesis of vitamin A by Pd-catalyzed
cross-coupling reactions, see: a) E. Negishi, Z. Owczarczyk, Tetrahe-
dron Lett. 1991, 32, 6683–6686. Selected papers on the Negishi reac-
tion: b) F. Zeng, E. Negishi, Org. Lett. 2001, 3, 719–722; c) B. H.
Lipshutz, G. C. Clososki, W. Chrisman, D. W. Chung, D. B. Ball, J.
Howell, Org. Lett. 2005, 7, 4561–4564; d) E. Negishi, G. Wang, H.
Rao, Z. Xu, J. Org. Chem. 2010, 75, 3151–3182. Selected papers on
the Suzuki reaction: e) A. Torrado, B. Iglesias, S. Lꢀpez, A. R.
de Lera, Tetrahedron 1995, 51, 2435–2454; f) A. R. de Lera, B. Igle-
sias, J. Rodrꢁguez, R. Alvarez, S. Lꢀpez, X. Villanueva, E. Padrꢀs, J.
Am. Chem. Soc. 1995, 117, 8220–8231; g) J. Uenishi, R. Kawahama,
O. Yonemitsu, A. Wada, M. Ito, Angew. Chem. 1998, 110, 334–336;
Angew. Chem. Int. Ed. 1998, 37, 320–323; h) Y. Pazos, A. R.
de Lera, Tetrahedron Lett. 1999, 40, 8287–8290; i) Y. Pazos, B. Igle-
sias, A. R. de Lera, J. Org. Chem. 2001, 66, 8483–8489; j) J. Uenishi,
K. Matsui, A. Wada, Tetrahedron Lett. 2003, 44, 3093–3096; k) S.
ꢇlvarez, Y. Pazos-Randulfe, H. Khanwalkar, P. Germain, R. Alvar-
ez, H. Gronemeyer, A. R. de Lera, Bioorg. Med. Chem. 2008, 16,
9719–9728. Selected papers on the Stille reaction: l) R. Alvarez, B.
Iglesias, S. Lꢀpez, A. R. de Lera, Tetrahedron Lett. 1998, 39, 5659–
5662; m) J. Thibonnet, G. Priꢈ, M. Abarbri, A. DuchÞne, J.-L. Par-
rain, Tetrahedron Lett. 1999, 40, 3151–3154; n) B. Domꢁnguez, B. Ig-
lesias, A. R. de Lera, Tetrahedron 1999, 55, 15071–15098; o) B.
Domꢁnguez, Y. Pazos, A. R. de Lera, J. Org. Chem. 2000, 65, 5917–
5925; p) A. Wada, K. Fukunaga, M. Ito, Synlett 2001, 0800–0802;
q) A. Wada, K. Fukunaga, M. Ito, Y. Mizuguchi, K. Nakagawa, T.
Okano, Bioorg. Med. Chem. 2004, 12, 3931–3942; r) A. Wada, N.
Matsuura, Y. Mizuguchi, K. Nakagawa, M. Ito, T. Okano, Bioorg.
Med. Chem. 2008, 16, 8471–8481; s) T. Okitsu, K. Iwatsuka, A.
Wada, Chem. Commun. 2008, 6330–6332.
[11] For general references, see: a) S. Siegel in Comprehensive Organic
Chemistry, Vol. 8 (Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack),
Pergamon, Oxford, 1991, Chapter 3.1; b) H. Takaya, R. Noyori,
Comprehensive Organic Chemistry, Vol. 8 (Eds.: B. M. Trost, I.
Fleming, M. F. Semmelhack), Pergamon, Oxford, 1991, Chapter 3.2;
c) D. J. Pasto in Comprehensive Organic Chemistry, Vol. 8 (Eds.:
B. M. Trost, I. Fleming, M. F. Semmelhack), Pergamon, Oxford,
1991, Chapter 3.3.
[12] a) H. Lindlar, Helv. Chim. Acta 1952, 35, 446–450; b) H. Lindlar, R.
Dubuis, Org. Synth. Coll. 1973, 5, 880–883.
[13] a) L. Brandsma, W. F. Nieuwenhuizen, J. W. Zwikker, U. Mꢉeorg,
Eur. J. Org. Chem. 1999, 775–779; b) D. Kaufman, E. Johnson,
M. D. Mosher, Tetrahedron Lett. 2005, 46, 5613–5615.
[24] A. Fꢅrstner, M. Bonnekessel, J. T. Blank, K. Radkowski, G. Seidel,
F. Lacombe, B. Gabor, R. Mynott, Chem. Eur. J. 2007, 13, 8762–
8783.
[25] A stereodivergent hydrosilylation, catalyzed by a cyclopentadienyl–
cobalt complex with a pendant phosphane donor, has led to exclu-
sive syn addition with triethylsilane and predominant anti-stereose-
lectivity with triethoxysilane. However, only moderate yields were
obtained with unsymmetrical internal alkynes, see: L. Yong, K. Kir-
leis, H. Butchenschçn, Adv. Synth. Catal. 2006, 348, 833–836.
[26] a) S. Lꢀpez, V. Rodrꢁguez, J. Montenegro, C. Saꢂ, R. Alvarez, C. S.
Lꢀpez, A. R. de Lera, R. Simꢀn, T. Lazarova, E. Padrꢀs, ChemBio-
Chem 2005, 6, 2078–2087; b) C. Silva, O. Nieto, S. Lꢀpez, A. R.
de Lera, J. Comput. Chem. 2006, 27, 116–123; c) S. Lꢀpez, J. Monte-
negro, C. Saꢂ, J. Org. Chem. 2007, 72, 9572–9581; d) J. Montenegro,
J. Bergueiro, C. Saꢂ, S. Lꢀpez, Org. Lett. 2009, 11, 141–144; e) J.
Bergueiro, J. Montenegro, F. Cambeiro, C. Saꢂ, S. Lꢀpez, Chem.
Eur. J. 2012, 18, 4401–4410.
[27] We keep cis and trans terminology to refer to the polyene skeleton,
although according to the sequence rules, compounds 9 and 14 are
in fact the E and the Z isomers, respectively.
[28] Although few cases of regioselectivity in hydrosilylation of unsym-
metrical internal alkynes have been reported, Molander et al. found
that a branching methyl group a to the alkyne provided sufficient
steric differentiation in the cis-selective hydrosilylation of alkynes
with phenylsilane when using a organoyttrium complex, see: G. A.
Molander, W. H. Retsch, Organometallics 1995, 14, 4570–4575.
[29] For a recent example of rhodium-catalyzed dehydrogenative Si,O
coupling by using a chiral silane and its application to the kinetic
resolution of nitrogen-donor-functionalized alcohols, see: H. F. T.
Klare, M. Oestreich, Angew. Chem. 2007, 119, 9496–9499; Angew.
Chem. Int. Ed. 2007, 46, 9335–9338.
[30] a) S. V. Maifeld, R. L. Miller, D. Lee, Tetrahedron Lett. 2002, 43,
6363–6366; b) S. V. Maifeld, M. N. Tran, D. Lee, Tetrahedron Lett.
2005, 46, 105–108.
[31] Although Alami et al. reported that removal of an excess amount of
silane was necessary for better stereoselectivity (see Ref. [21]), in
our case this was not so, because 12 was obtained without detectable
isomerization.
[14] For previous syntheses, see: H. Hopf, N. Krause, Tetrahedron Lett.
1985, 26, 3323–3326, and also ref. [10a].
[15] W. Oroshnik, J. Am. Chem. Soc. 1956, 78, 2651–2652.
[32] a) J. C. Gilbert, D. H. Giamalva, J. Org. Chem. 1985, 50, 2586–2587;
b) T. J. Barton, N. Tillman, J. Am. Chem. Soc. 1987, 109, 6711–6716.
[33] R. J. Mills, V. Snieckus, J. Org. Chem. 1983, 48, 1565–1568.
[34] Prepared by drying commercial TBAF·3H2O with molecular sieves
followed by addition of 25% w/w D2O.
[16] Starting material and/or over-reduction of the conjugated double
bonds were also obtained, see: a) B. Borhan, M. L. Souto, J. M. Um,
B. Zhou, K. Nakanishi, Chem. Eur. J. 1999, 5, 1172–1175; b) M.
Souto, J. Um, B. Borhan, K. Nakanishi, Helv. Chim. Acta 2000, 83,
2617–2628; c) Y. Fujimoto, J. Ishihara, S. Maki, N. Fujioka, T.
Wang, T. Furuta, N. Fishkin, B. Borhan, N. Berova, K. Nakanishi,
Chem. Eur. J. 2001, 7, 4198–4204; d) N. Nesnas, R. R. Rando, K.
Nakanishi, Tetrahedron 2002, 58, 6577–6584.
1
[35] In the H NMR spectrum of 11-D-12, the signal for H12 disappears,
and H10 and H12 appear as two singlets at d=5.88 and 6.53 ppm,
respectively. In the spectrum of 11,12-D2-12, the signals for H11 and
H12 disappear and H10 appears as a singlet at d=6.53 ppm.
[36] The occurrence of protodesilylation with no deuterium incorpora-
tion even when TBAF·3D2O was used has been attributed to a
Hoffman-like elimination by abstraction of a proton from tetrabuty-
lammonium cation, with generation of tributyl amine and butene;
see: W. M. Seganish, Development of aryl siloxane cross-coupling
technology and its application to the synthesis of colchicine and allo-
colchicine derivatives. Ph.D. Dissertation, University of Maryland,
College Park, 2005.
[17] When these conditions were used to reduce [9,10-13C2]-11,12-didehy-
droretinol to [9,10-13C2]-11Z-retinol, a Z/E ratio at C11 of 3:1 was
observed: N. J. McLean, A. Gansmuller, M. Concistre, L. J. Brown,
M. H. Levitt, R. C. D. Brown, Tetrahedron 2011, 67, 8404–8410.
[18] B. Marciniec in Hydrosilylation: A Comprehensive Review on Recent
Advances, Advances in Silicon Science 01 (Ed.: J. Matisons), Spring-
er, Poznan, Poland, 2009.
[19] T. Sanada, T. Kato, M. Mitani, A. Mori, Adv. Synth. Catal. 2006,
348, 51–54.
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

S. Lꢀpez et al.
[37] Reactions and purification of final products were carried out in the
absence of light. Purification of the acid-sensitive cis-retinoids was
carried out by flash chromatography by using neutral alumina as the
adsorbent.
[38] Fꢅrstner etal. reported that this reaction was not rigorously trans-se-
lective when applied to 1,3-enynes, having observed appreciable
amounts of a cis isomer in his total synthesis of myxovirescin A1,
see Ref. [24].
[39] Y. Wang, J. Lugtenburg, Eur. J. Org. Chem. 2004, 5100–5110.
[40] Trost and co-workers have demonstrated that the cross-coupling of
sterically hindered trisubstituted benzyldimethylsilanes proceeds
well under palladium catalysis: B. M. Trost, M. R. Machacek, Z. T.
Ball, Org. Lett. 2003, 5, 1895–1898.
Received: June 26, 2012
Published online: && &&, 0000
&
8
&
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 11-cis-Retinoids
FULL PAPER
Cross-Coupling Reactions
J. Bergueiro, J. Montenegro, C. Saꢀ,
S. Lꢁpez* ...................... &&&& — &&&&
Synthesis of 11-cis-Retinoids by
Hydrosilylation–Protodesilylation of
an 11,12-Didehydro Precursor: Easy
Access to 11- and 12-Mono- and 11,12-
Dideuteroretinoids
Reduction to retinoids: An expeditious
approach to 11-cis-retinoids was ach-
ieved on the basis of semireduction of
a readily available 11-yne precursor
through a highly efficient hydrosilyla-
tion–protodesilylation protocol (see
scheme). The complete selectivity of
the method also allowed direct access
to 11- and 12-mono-, and 11,12-dideu-
tero-11-cis-retinoids.
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!